A revised intracarotid etomidate memory (Wada) procedure

A revised intracarotid etomidate memory (Wada) procedure
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  A revised intracarotid etomidate memory(Wada) procedure Andelman F, Kipervasser S, Maimon S, Fried I, Parmet Y, NeufeldMY. A revised intracarotid etomidate memory (Wada) procedure.Acta Neurol Scand: 2013: 127: 97–102. ©  2012 John Wiley & Sons A/S. Objectives –   To evaluate unilateral memory function by the means of a modified Montreal etomidate speech and memory procedure (e-SAM) in epilepsy patients who were candidates for standard anteriortemporal lobectomy involving resection of mesial temporal lobestructures.  Materials and methods –   After the first three patientsexperienced significant side effects with the e-SAM procedure, wemodified the procedure to a single bolus injection. Theneuropsychological data of all 21 patients who underwent unilateralmemory testing by means of intracarotid injection of etomidate wereanalyzed.  Results –   There was a significant difference in memoryscores when injections were on the side ipsilateral to the epileptogenicfocus compared with when the injections were on the contralateralside ( P  <  0.01), supposedly reflecting unilateral hippocampal memoryfunction and dysfunction. In addition, the procedural modificationresulted in eradication of all major side effects in the ensuing 18patients.  Conclusions –   The technical modification of the Montrealprocedure from continuous to bolus injection effectively enabled thedemonstration of the relative weakness of the memory function of theepileptogenic hemisphere. The revised etomidate procedure providedthe clinical information on unilateral hippocampal memory functionnecessary for surgical decision. F. Andelman 1 , S. Kipervasser 2,3 ,S. Maimon 4 , I. Fried 1,3,5 , Y.Parmet 6 , M. Y. Neufeld 2,3 1 Functional Neurosurgery Unit, Department ofNeurosurgery, Tel Aviv Medical Centre, Tel Aviv, Israel; 2 EEG and Epilepsy Unit, Department of Neurology,Tel Aviv Medical Centre, Tel Aviv, Israel;  3 The SacklerFaculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4 Department of Neurosurgery, Tel Aviv Medical Center,Tel Aviv, Israel;  5 Division of Neurosurgery, University ofCalifornia, Los Angeles, CA USA;  6 Department ofIndustrial Engineering and Management, Ben-GurionUniversity, Beersheba, IsraelKey words: etomidate; hippocampal function; memory;Wada testFani Andelman, PhD, Functional Neurosurgery Unit,Tel-Aviv Sourasky Medical Center, 6 Weitzman Street,Tel-Aviv 64239, IsraelTel: +9723-697-3107Fax: +9723-697-3992e-mail: for publication May 4, 2012 Introduction The intracarotid amobarbital procedure (theWada test) has been traditionally used to deter-mine cerebral language dominance and unilateralmemory potential in candidates for epilepsy sur-gery (1  –  4). However, the risk factors associatedwith angiography, the lack of prospective validitystudies, and the emergence of noninvasive meth-ods, such as functional magnetic resonance imag-ing (fMRI), have led to a division amongclinicians regarding the role of the invasive Wadaprocedure in the presurgical evaluation of candi-dates who have temporal lobe epilepsy (TLE)(5  –  13). Baxendale et al. (5,6) reported that themajority of epilepsy surgery centers no longeradvocate the Wada procedure for all TLE candi-dates. Other studies (14  –  16) suggested that func-tional MRI and high-quality structural MRIaccompanied by a thorough neuropsychologicalassessment can replace the Wada test in manycases .  For example, Bonelli et al. (15) claim thatit is the functional capacity of the posterior partof the ipsilateral hippocampus that had the high-est correlation with postoperative memory encod-ing. However, the authors concur that theimaging parameters still need to be improved forthe neurosurgeons to rely on functional imagingas a predictor of postoperative memory decline.The consequences of resection of functional tis-sue can be significant particularly in cases of MRI negative dominant TLE, and its resection isusually avoided (17  –  19). Despite the controversyand the differences in protocols across centers,the Wada test still remains the only method toreliably identify unilateral functional tissue of themedial temporal lobes. For this reason, eventhose epilepsy centers that do not advocate rou-tine Wada testing on all TLE surgical candidatestend to perform the Wada test for unilateral 97 Acta Neurol Scand 2013: 127: 97–102 DOI: 10.1111/j.1600-0404.2012.01685.x    2012 John Wiley & Sons A/S  ACTA NEUROLOGICASCANDINAVICA  memory assessment in selected patients (11). Cur-rent clinical indications for the use of the Wadatest in presurgical patients who are candidates forantero-medial temporal resection include left epi-leptogenic focus coupled with an absence of MRIlesion in the dominant hemisphere and unim-paired memory on baseline neuropsychologicalassessment. Wada testing is indicated if routineneuropsychological memory testing is suggestiveof functional disruption contralateral to a knownlesion in absence of concomitant structural evi-dence. Additional reasons for Wada testinginclude structural lesions contralateral to the epi-leptogenic hippocampus, left-handedness withsigns of ‘crowding’ and ambiguous or bilaterallanguage test results on fMRI and pervasive ver-bal and visual memory deficits on baseline neuro-psychological testing coupled with bilateralhippocampal lesions as seen on MRI. In this con-text, the Wada test can provide the critical infor-mation necessary for surgical decision making,with clinical decisions being made on a case-by-case basis to ensure an appropriate risk  –  benefitratio for every patient (6).Most Wada tests in North America are beingperformed with Amytal. We started using Etomi-date in 2007 because of the difficulty in Amytalsupply outside the United States. Etomidate, animidazole derivative and a potent non-barbituratehypnotic agent with no analgesic properties, shortduration of action, and minimal hemodynamiceffects, was first used in the Wada procedure byJones-Gotman et al. (20) at the Montreal Neuro-logical Institute (MNI), with tremor and shiver-ing as side effects. Other side effects have beenrecently reported, and they include myoclonusand seizures (21). The procedure applied at MNIincludes a bolus injection followed by a continu-ous application of etomidate via an infusionpump for as long as needed to test the languageand memory functions (20).We encountered significant side effects at ourcenter when applying the MNI procedure accord-ing to the published algorithm (20). This experi-ence led to our decision to modify the originalprocedure by switching the continuous infusionof the drug to a single bolus injection only. Ouraim was to investigate whether an intracarotidbolus injection of etomidate would allow an ade-quate length of hemiparesis for the purpose of speech and memory testing, provide the sameinformation on unilateral hippocampal memoryfunction as continuous administration via aninfusion pump, and do so without side effects. If this is found to be the case, etomidate, an easilyavailable drug, could be a good alternative toAmytal in Wada testing. This study is a report of our experience with the technically modified in-tracarotid etomidate speech and memory test (e-SAM) procedure. Material and methods Subjects This retrospective study was approved by the Tel-Aviv Sourasky Medical Center ethics committeereview board. All the participants were adultswith TLE who were candidates for standard ante-rior temporal lobectomy involving resection of mesial temporal lobe structures for removalof the epileptogenic focus by the same neurosur-geon (I.F.). The patients underwent bilateralWada tests to determine cerebral language domi-nance and unilateral memory potential. Fourteenpatients with left epileptic focus and sevenpatients with right epileptic focus underwent theWada test with the use of etomidate, and theirresults were analyzed. The laterality of the epilep-tic focus was determined by concordance of results of video-electroencephalographic (vEEG)monitoring, structural magnetic resonance imag-ing (MRI), and neuropsychological examinationincluding the patients’ performance on material-specific tests of learning and memory. All thepatients had undergone a comprehensive neuro-psychological assessment that included measuresof general intelligence, learning and memory, lan-guage, perceptual, motor, and executive functionsas well as screening for psychopathology. Rele-vant patient characteristics are presented inTable 1. Measures Standardized memory assessment –   The results of the standardized Hebrew version of the ReyAuditory Verbal Learning Test (RAVLT) (22)and the Rey Complex Figure Test (RCFT) (23)were used for analysis. Scores for total learningof 15 words (RAVLT_T, representing the sum of the first five trials), RAVLT_5 (5th trial score),and RAVLT_8 (the score of the 8th trial) as wellas the long-term recall of the RCFT were used aslearning and memory indices. Intracarotid etomidate procedure –   The patientsunderwent the intracarotid procedure accordingto the protocol developed at the Sourasky Medi-cal Center (24) that had been previously appliedto amobarbital (25) and methohexital (26) at thesame center. After an examination of the vascular 98 Andelman et al.  anatomy, a catheter was placed in the internalcarotid artery by means of a transfemoralapproach. None of the patients exhibited evi-dence of anomalous vascularization. Two intra-carotid injections, one into each hemisphere, of the drug were administered manually by an inter-ventional neuroradiologist using a catheter viathe femoral artery. The order of injections wasdetermined by clinical considerations, with thehemisphere with the epileptic focus being injectedfirst. The second hemisphere was injected immedi-ately after completion of memory testing of thefirst hemisphere.The drug dosage given to the first threepatients was based on the published e-SAM for-mula of continuous injection, namely thesepatients have received 2 mg initial bolus of etomi-date injected by infusion pump and followed by acontinuous infusion (0.003  –  0.004 mg/kg/minute)at a rate of 6 ml/h (20). Because of the severeside effects that these patients have experienced,we have changed the e-SAM procedure from con-tinuous to a bolus injection only. A bolus of 2 mg etomidate diluted with 4 cc of saline solu-tion was injected into each hemisphere over 60 sstarting with the fourth patient. The signs of hemiparesis usually appeared by 40 s after theinitiation of the injection while complete hemipa-resis was reached by 60 s and lasted for an aver-age of five minutes. Examination of speechfunction and presentation of eight objects formemorization was performed by the neuropsy-chologist during 150  –  180 s, well within the dura-tion of complete hemiparesis that was checked byan attending neurologist every 30 s (Table 1). Allmemory stimuli were presented while the drugwas active based on the clinical assessment. Theduration of drug action reliably exceeded theduration of speech testing and presentation of allmemory objects in the patients. Real objectsrather than pictures or printed words were usedat our center to eliminate verbal encoding prob-lems during dominant injection (27). Testing formemory started upon complete resolution of thehemiparesis and full return of neurological func-tion. The second hemisphere was injected imme-diately after the testing of the first hemispherewas completed. The same procedure with differ-ent memory test items was applied.Two clinical memory scores and a memoryasymmetry score were computed for the purposesof this study. The ipsilateral and contralateralrecognition memory results comprised the clinicalscores, which were the number of correct itemsrecognized out of eight targets and 16 foils. Amemory asymmetry score was added as a tool for Table 1  Characteristics of individual patients and their Wada parametersPt. Age Gender Hand.Educ.(y)Age atonset (y)LesionsideMTS(MRI)% LeftMemory% RightMemory% Memoryasymmetry Lang. Lat.Hemidurationleft (s)Hemi.durationright (s)1 34 F Left 12 0 Left No 0 75 75 Right 580 5402 26 M Right 10 14 Left No 87.5 0 87.5 Left 480 4803 34 M Right 12 11 Left Yes 25 87.5 62.5 Bi-lat 480 5404 24 F Left 10 4.5 Right Yes 75 0 75 Left 540 5405 25 F Left 14 17 Right No 62.5 100 37.5 Right 320 4206 33 F Right 12 28 Left Yes 62.5 12.5 50 Left 600 4207 24 M Right 12 20 Left No 0 100 100 Left 330 3308 54 F Right 12 29 Left Yes 62.5 87.5 25 Left 900 7209* 36 F Right 11 16 Bi-lat Yes 0 0 0 Left 420 48010 18 F Left 12 10 Right No 75 50 25 Left 465 51011 21 M Right 10 0.75 Left Yes 0 100 100 Left 180 22012 29 M Left 12 11 Right Yes 100 25 75 Left 400 30013 18 M Right 12 12 Left No 37.5 87.5 50 Left 445 45014 30 F Right 12 16 Left Yes 25 87.5 62.5 Left 540 42015 32 F Right 15 27 Right No 62.5 50 12.5 Left 420 36016 34 M Right 11 22 Left No 62.5 100 37.5 Left 450 39017 38 F Right 17 38 Left No 100 100 0 Left 330 44018 17 F Right 11 12 Left No 50 87.5 37.5 Left 660 48019 19 F Right 12 1 Left Yes 37.5 100 62.5 Left 420 42020 18 F Right 12 14 Left No 25 100 75 Left 420 46021 33 F Right 15 16 Right No 100 75 25 Left 300 380Mean 28.4 33.3% (M) 23.8% (Left) 12.19 15.20 66.7% (Left) 57.1% (Yes) 50.0 67.86 51.19 85.7% (Left) 461 443Pt., patient; Hand., handedness; Educ., years of education; MTS, mesial temporal sclerosis; MRI, magnetic resonance imaging; Lang. lat., language lateralization; Hemi.,hemiparesis;% memory left or right, percentage of correct memory responses;% asymmetry, difference between percentage of left and right memory performance;*Patient 9: bilateral lesions on MRI, including right MTS and left hippocampal cyst, her video electroencephalogram showed right ictal onset. Other patients: side oflesion on MRI was concordant with side of VEEG ictal onset. 99 Revised etomidate memory  statistical analysis of memory function (28).Asymmetry scores were calculated as the contra-lateral (i.e., opposite to the epileptogenic focus)minus the ipsilateral Wada memory score. Thesescores were converted to percentages that wereused for analyzing any discrepancy in memoryfunction between the epileptogenic hemisphereand the non-epileptogenic hemisphere (Table 1).Memory scores of the patient groups with leftand the right epileptogenic focus were statisticallyanalyzed and compared. Statistical analysis –   A series of one-way analysisof variance (ANOVA) was performed to examinethe group differences for the demographic vari-ables. Another series of one-way ANOVAs wasperformed to examine the group differences onthe standard neuropsychological and Wada mem-ory scores. A two-way ANOVA for examininglesion lateralization and memory function of thesides ipsilateral and contralateral to the epilepticfocus hemisphere was performed. The Pearsoncorrelation coefficient was used to examine therelationships between the Wada memory scores,the neuropsychological test performance scores,and the demographic variables. A  P  value of  < 0.05 was considered to be statistically signifi-cant . Results The first three patients had been administeredetomidate by continuous infusion of the drug andsuffered significant side effects. Specifically, thefirst patient experienced a severe seizure with sec-ondary generalization, the second patient had aprolonged period of obtundation, and all the firstthree patients suffered from severe tremor andmyoclonus. After we switched to a protocol of administering a single bolus injection of the drug,none of the succeeding 18 patients displayed anysimilar major side effects.The results of the univariate analyses revealedno significant demographic differences among the21 patients in the study cohort (Table 1). One-way ANOVA of the standard neuropsychologicalmemory tests revealed a significant difference inthe ‘best learning’ measure of RAVLT-5 betweenpatients with left and right epileptic focus: theformer had significantly lower verbal memoryability ( M   =  10.08, SD  =  2.06) than the latter( M   =  12.17, SD  =  .98) ( P  =  0.03) (Table 2).A significant negative Pearson correlation(  0.59,  P  =  0.005) between the age of onset of epilepsy and the memory asymmetry score wasobserved: the earlier the onset of epilepsy thehigher the asymmetry score, reflecting the differ-ence in unilateral hippocampal memory perfor-mance as a function of duration of epilepsy.A two-way ANOVA was performed to examinethe differences in unilateral hemispheric memoryabilities during the Wada testing between thepatients with left and right epileptic focus: theformer had a significantly lower percentage of memory function ( M   =  41.07, SD  =  31.56) thanthe latter ( M   =  50.00, SD  =  35.35) ( P  =  0.01).There was no significant difference between thesetwo patient groups in the contralateral memoryperformance as measured by percent of recog-nized items for the patients with left ( M   =  80.35,SD  =  32.42) and with right ( M   =  79.17, SD  = 17.08) epileptic focus (Table 3). A significantinteraction between lesion lateralization and later-alized memory function was found ( P  <  0.01).The memory function of the ipsilateral hemi-sphere in the patients with left hemisphere epilep-tic focus was significantly lower than that of thepatients with right hemisphere epileptic focus(Fig 1).Taken together, the results showed that, in theabsence of significant differences in demographicvariables between these two patient groups, thedifferences that were detected in unilateral mem-ory performance were probably due to the effectof the epileptogenic lesion. The results of ourstudy also suggest that the modified e-SAM Table 2  Mean neuropsychological test performance of the patients by lesionlateralizationSide of lesion RAVLT-5 RAVLT-total RAVLT-8 RCF-LTMLH ( n   =  14) 10.08 (2.06) 45.62 (8.59) 7.23 (3.52) 12.79 (6.46)RH ( n   =  7) 12.17 (0.98) 50.67 (3.01) 9.33 (2.07) 14.08 (5.54)Significance  *P   =  0.03  P   =  0.18  P   =  .19  P   =  0.68The numbers in the parentheses represent standard deviations.LH, left hemisphere epileptic focus; RH, right hemisphere epileptic focus (includ-ing the patient with right VEEG onset); RAVLT-5, fifth trial of the Rey AuditoryVerbal Learning Test; 19RAVLT-Total, sum of five learning trials of the Rey Test;RAVLT-8, delayed recall of the Rey Test; RCF-LTM, long-term recall of the ReyComplex. Table 3  Mean etomidate Wada memory scores of the patients by lesionlateralizationLeft hemispherememoryRight hemispherememoryMemoryasymmetryLH 41.07 (31.56) 80.35 (32.42) 58.92 (28.35)RH 79.17 (17.08) 50.00 (35.35) 41.67 (27.0)All patients* 51.19 (30.08)*Patient 9 with bilateral medial temporal lesions omitted; the numbers in theparentheses represent standard deviations; LH, left hemisphere epileptic focus;RH, right hemisphere epileptic focus. 100 Andelman et al.  procedure with the use of a single initial bolusfor administering etomidate not only provides thenecessary information on unilateral hippocampalmemory function but it emerged as being associ-ated with an increased tolerability to etomidate interms of almost complete eradication of the sideeffects displayed with continuous administrationby the infusion pump. Discussion The main contribution of the current study is thedemonstration of a modification of the approachfor applying the previously described intracarotidetomidate injection the e-SAM procedure. Weswitched from a continuous infusion of the drugto an initial bolus injection only, and this changesignificantly decreased the extent of untowardside effects among the patients who underwentthe modified etomidate Wada testing, withoutloss of neuropsychological information.Clinical impressions of intracarotid etomidatememory testing and the results of the statisticalanalysis showed that the modified e-SAM proce-dure adequately demonstrated the unilateral hip-pocampal memory function in our sample of patients. A comparison of the Wada memoryasymmetry scores in patients who received etomi-date with our previously published data (25,26)at the same center revealed that the asymmetryscore obtained with etomidate ( M   =  51.19,SD  =  30.08) was comparable to that of amobar-bital ( M   =  51.09, SD  =  28.98) but not of metho-hexital ( M   =  37.37, SD  =  32.08). This finding issuggestive of the tendency of etomidate to behavelike amobarbital in revealing unilateral hippo-campal memory function and dysfunction, asreflected by the asymmetry score (28). The findingof a significant interaction between lesion laterali-zation and lateralized memory function (Fig 1),suggests that patients with left hemisphere epilep-togenic lesion showed on average a significantlylower memory of the ipsilateral hemisphere com-pared with the patients with right hemisphere epi-leptogenic lesion confirming clinical impressions.One advantage in using etomidate (versus amy-tal), in addition to its availability and minimalside effects when administered as a bolus only,was a reliable onset of hemiplegia (almost invari-ably after 40 s), its adequate duration for thepurposes of memory testing and a short period of recovery.Three etomidate patients in our sample failedthe Wada memory test and for this reason under-went vagal nerve stimulation rather than resectivesurgery. One of these patients failed the memorytest bilaterally (patient #9 in Table 1 who hadbilateral hippocampal lesions on MRI and righttemporal onset of epilepsy on vEEG). Twopatients showed reversed asymmetry with ade-quate ipsilateral and inadequate contralateralmemory scores (patients #2 and #6).Seventeen patients have undergone anteriortemporal lobectomy without reporting significantpostoperative memory deficits. Several patientsafter surgery in the dominant hemispherereported mild postoperative memory decline: theywere referred to memory training after a brief screening. Two patients are awaiting surgery. Asnot all patients have undergone a formal postop-erative neuropsychological assessment, a system-atic analysis of preoperative versus postoperativememory function has not yet been performed.Notably, the patients with reversed memoryasymmetry scores did not experience prolongedspeech arrest, in contrast to the findings reportedin Mani et al. (27) study in which left TLEpatients’ reversed asymmetry was explained byprolonged speech arrest after the dominant hemi-sphere injection. It is possible that their patients’memory results were reflective of language encod-ing problems after dominant injections, becausethose investigators used verbal stimuli for testingmemory. To avoid any confounding effects of verbal stimuli, we used real objects to assessmemory in all our Wada studies.In sum, the technical modification of the Mon-treal procedure from continuous to bolus injectionadopted at our center resulted in a state of hemipa-resis long enough for speech and memory testing,the concomitant abolishment of severe side effects,and effectively enabled the demonstration of the Figure 1.  Interaction between lesion lateralization and later-alized memory function during etomidate Wada testing:patients with left hemisphere epileptogenic lesion show a sig-nificantly lower memory of the ipsilateral hemisphere com-pared with the patients with right hemisphere epileptogeniclesion. Dashed line  –   left hemisphere memory performance,Solid line  –   right hemisphere memory performance. 101 Revised etomidate memory
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